ABSTRACT Cancer-related cognitive decline (CRCD) is a highly feared and prevalent outcome for the growing population of older cancer survivors. Education is known to predict better cognitive function in older adults generally and substantially reduces dementia risk, but is largely unexplored in the general population of older cancer survivors. Almost all CRCD studies are conducted in clinical settings with highly educated study populations, and thus are often not well suited to evaluate the effects of education as a CRCD risk-modifying factor. This is a major evidence gap limiting our understanding of the burden or predictors of CRCD at the population level. The proposed research leverages the cognitive reserve theory, which postulates that cognitive reserve allows individuals to maintain cognitive function despite accumulating brain pathology and cognitive insults. Our central hypothesis is that education and related cognitive reserve markers will modify the rate of memory change associated with a new cancer diagnosis and chemotherapy receipt, which may be cognitive insults, in mid-to-later life. We will investigate whether the course of CRCD is altered in middle-aged and older cancer survivors with high cognitive reserve (measured by education, numeracy, occupational skill, social engagement), relative to those with low reserve and age-matched cancer-free adults. The specific aims are to: 1) determine the rate of memory change associated with a new cancer diagnosis, according to education and related markers of pre-cancer diagnosis cognitive reserve, and 2) determine the rate of memory change associated with chemotherapy receipt, overall and according to education and related markers of pre-cancer diagnosis cognitive reserve. We will use data from the nationally representative US Health and Retirement Study and linked Medicare data from 1998-2016. Segmented linear mixed models will estimate memory change prior to and after a new cancer diagnosis and treatment across levels of cognitive reserve markers, with age-matched cancer-free adults as a comparison group. Key innovations are: 1) our use of longitudinal pre-cancer diagnosis data that have been previously unavailable in prior clinic-based studies of CRCD; 2) a large nationally-representative study population with diverse variation in education and other cognitive reserve markers that allows generalizability of results; 3) our linkage of the rich HRS data to Medicare claim data as a gold standard for information on cancer treatments; 4) our leveraging of cognitive reserve theory from the Alzheimer?s and dementia field to help understand the phenomenon of CRCD. Bridging the fields of cancer and aging epidemiology, our results will: 1) advance understanding of CRCD, a critically important outcome to cancer patients and their families, and 2) enhance understanding of the neurocognitive effects of education and mechanisms of cognitive reserve, by evaluating whether cognitive reserve applies to this non- dementia neuropathological phenomenon. This research is a first step towards achieving our long-term goal of understanding and improving cognitive aging outcomes in the growing population of older cancer survivors.